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Tiragolumab
Monoclonal antibody From Wikipedia, the free encyclopedia
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Tiragolumab (development names RG6058 and MTIG7192A) is a humanized monoclonal antibody that functions as an immune checkpoint inhibitor by targeting the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) pathway.[1][2] Developed by Genentech and Roche, the drug is designed to enhance anti-tumor immune responses when used in combination with other immunotherapy agents, particularly atezolizumab (Tecentriq).[1]
In January 2021, tiragolumab received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for use in combination with atezolizumab in the treatment of patients with PD-L1-high metastatic non-small-cell lung cancer (NSCLC) who do not harbor EGFR mutations or ALK rearrangements.[3]
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Mechanism of action
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that specifically binds to TIGIT, preventing its interaction with its primary ligand, the poliovirus receptor (PVR, also known as CD155).[4] TIGIT is an inhibitory immune checkpoint receptor primarily expressed on T cells and natural killer (NK) cells that normally suppresses anti-tumor immune responses through multiple mechanisms.[5]
The therapeutic mechanism of tiragolumab involves blocking the TIGIT-PVR interaction, which normally leads to T cell inhibition and immune suppression in the tumor microenvironment.[6] By preventing this inhibitory signaling, tiragolumab aims to restore and enhance anti-tumor T cell responses. Additionally, preclinical studies have demonstrated that tiragolumab surrogate antibodies can activate tumor-associated macrophages, monocytes, and dendritic cells through Fcγ receptors, leading to the transformation of exhausted CD8+ T cells into a more memory-like state with enhanced anti-tumor activity.[5]
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Clinical development
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Phase I studies
The initial clinical evaluation of tiragolumab was conducted through a Phase 1a/1b dose-escalation and dose-expansion study (GO30103, NCT02794571), which investigated both single-agent tiragolumab and its combination with atezolizumab in patients with advanced solid tumors.[7]
The study demonstrated that tiragolumab in combination with atezolizumab was tolerable and showed preliminary antitumor activity across various solid tumor types.[4][8][9][10]
Pharmacodynamic studies from the Phase I trial revealed that peripheral TIGIT receptors on CD8+ T cells were completely occupied for sustained periods at tiragolumab doses of at least 30 mg administered every three weeks, with clinical activity observed at doses ranging from 400 mg to 600 mg every three weeks.[11]
Phase II CITYSCAPE trial
The pivotal Phase II CITYSCAPE trial (NCT03563716) was a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of tiragolumab in combination with atezolizumab as first-line therapy in patients with PD-L1-positive advanced NSCLC.[12][13] This study represented the first randomized investigation in the anti-TIGIT therapeutic field and enrolled a total of 135 patients.[14][15]
The CITYSCAPE trial provided the first evidence of enhanced anti-tumor activity when targeting both TIGIT and PD-L1 immune inhibitory receptors simultaneously, potentially amplifying the immune response against tumors.[16] The encouraging efficacy and safety results from this trial formed the basis for the FDA's breakthrough therapy designation.[1][17]
Other clinical investigations
Tiragolumab has also been investigated in other malignancies, including small-cell lung cancer (SCLC) through the SKYSCRAPER-02 trial and esophageal cancer.[11][18]
Additionally, dedicated studies have been conducted to evaluate the drug's safety and efficacy in Japanese patients with advanced or metastatic solid tumors.[19]
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Regulatory status
In January 2021, the FDA granted breakthrough therapy designation to tiragolumab in combination with atezolizumab for the treatment of patients with metastatic NSCLC whose tumors are PD-L1-high and do not harbor EGFR mutations or ALK rearrangements.[3] This designation was based on the results from the Phase II CITYSCAPE study, which demonstrated improved clinical outcomes in this patient population.[20][21]
See also
References
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